Simmons-Smith type reaction

The organoaluminum-mediated cyclopropanation had unique selectivity not observable in Simmons-Smith type reactions [95], Treatment of geraniol with i-Bu3Al (2 equiv.)-methylene iodide (1 equiv.) in CH2CI2 at room temperature for 5 h produced cyclopropanation products in 75 % combined yields in the ratio 76 1 4. Consequently, methylene transfer by the aluminum method occurs almost exclusively at the C(6)-C(7) olefinic site far from the hydroxy group of geraniol and the C(2) -C(3) ole-finic bond was left intact. In sharp contrast, the zinc method resulted in the opposite regioselectivity via hydroxy-assisted cyclopropanation, as shown in Sch, 62. 

The asymmetric synthesis of cyclopropanes has attracted continual efforts in organic synthesis, due to their relevance in natural products and biologically active compounds. The prevalent methods employed include halomethylmetal mediated processes in the presence of chiral auxiliaries/catalysts (Simmons-Smith-type reactions), transition-metal-catalyzed decomposition of diazoalkanes, Michael-induced ring closures, or asymmetric metalations [8-10,46], However, the asymmetric preparation of unfunctionahzed cyclopropanes remains relatively undisclosed. The enantioselective activation of unactivated C-H bonds via transition-metal catalysis is an area of active research in organic chemistry [47-49]. Recently, a few groups investigated the enantioselective synthesis of cyclopropanes by direct functionalization reactions. 

Kobayashi and coworkers reported catalytic asymmetric Simmons-Smith type reaction of allylic alcohols (Scheme 6.98). In this reaction, Lewis acid (R,R)-(112) prepared by premixing of (1R,2R)-cyclohexane bis-sulfonamide and i-Bu2AlH was found to realize good enantioselectivity. Since, in the similar reaction catalyzed by chiral Zn complex derived from (1R,2R)-cyclohexane bis-sulfonamide and Et2Zn instead of chiral aluminum complex, the same enantioselectivity was observed, chiral Zn carbenoid species formed from (R,R)-(112) and Et2Zn via Al-Zn transmetallation was proposed as an active species [117]. 

The Simmons-Smith-type cyclopropanation of olefins is one of the most well-known reactions of carbenes and carbenoids. However, cyclopropanation of simple olefins with magnesium carbenoids is usually very difficult and only cyclopropanation of allylic alcohols was reported. Thus, treatment of allylic alcohols (23) in CH2CI2 at —70°C with i -PrMgCl and diiodomethane for 48 to 60 h afforded cyclopropanes in up to 82% yield as a mixture of syn- and and-isomers. In this reaction, 5yn-isomers were mainly or exclusively obtained (synianti = 5 1-400 1) (equation 10). 

Cyclopropanation.1 CH2I2 is used in cyclopropanation of the Simmons-Smith type, but it is about 20 times more expensive than CH2Br2. CH2Br2 in combination with Zn/CuCl can be used for cyclopropanation, particularly when sonication is used to promote the heterogeneous reaction in ether. Reaction times are 2-4 hours, and yields range from 30-70%. 

Cyclopropanation of Allylic Alcohols. Simmons-Smith type cyclopropanation of the allylic alcohol 22 in the presence of a catalytic amount of the bis-sulfonamide la leads to formation of the corresponding cyclopropane 23 in high yield and selectivity (eq 6, Table 3). The reaction is rapid (< 1 h) and can be performed at low temperature (either 0 °C or —20 °C). Substrate scope encompasses both di- and tri-substimted allylic alcohols (24 and 26). However, substimtion at the 2 position, as in 28, leads to a drastic decrease in selectivity. The presence of additional oxygenated functionality (30) in the proximity of the alkene also lessens selectivity." The method is limited to the cyclopropanation of allylic alcohols. Other alkene-containing substrates, such as allylic ethers, homo-allylic alcohols and allylic carbamates, do not react with high selectivity. 

It is advantageous to utilize either titanium isopropoxide or trimethylaluminum complexes with aldehydes in general, because pinacol-coupled diols form with the Zn/CH2Br2/riG4 systems as minor side products. No evidence of Simmons-Smith-type side products was observed with any of the methylena-tion reagents. Additional examples of the reaction with aldehydes are presented in Table 11. 

The 2-oxabicyclo[3.1.0]hexane nucleoside 166 was obtained via a Simmons-Smith type cyclopropanation reaction of intermediate 164, followed by glycosidation with several natural heterocyclic bases <05JOC6891 05NNNA383>. A restricted version of puromycin built on a bicyclo[3.1.0]hexane template was synthesized by Choi via Mitsunobu coupling of a 3-azido-substituted carbocyclic moiety with 6-chloropurine to give compound 167 <02OL589>. 

Several procedures deal with optically active auxiliaries employed in stoichiometric amounts or more, but which are not covalently bonded to one of the reagents. These catalysts influence Simmons-Smith type cyclopropanations of allylic alcohols with moderate to excellent enantiose-lectivities. Whereas the reaction of ( )-3-phenyl-2-propen-l-ol (1) with diethylzinc and diiodo-methane in the presence of (17 ,25 )-A,-methylephedrine (2 equivalents) gives an enantiomeric excess of only 24% under optimized conditions107, the same reaction with (/ ,/f)-diethyl tartrate (1.1 equivalents) as ligand affords (1 ) ,27t)-fra i-l-hydroxymethyl-2-phenylcyclopropane (2) with up to 79% ee108, Similar results are achieved with the corresponding (Z)-olefin, and even higher enantioselectivities are obtained for dimethylphenylsilyl-substituted allylic alcohols such as 3109. 

Dimethylsulfonium methylide and dimethylsulfoxonium methylide also differ in their reachons with a,p-unsaturated carbonyl compounds. The sulfonium ylide reacts at the carbonyl group to form an epoxide, but with the sulfoxonium ylide a cyclopropane derivative is obtained by Michael addihon to the carbon-carbon double bond. The difference is again due to the fact that the kinehcally favoured reachon of the sulfonium yhde with the carbonyl group is irreversible, whereas the corresponding reaction with the sulfoxonium yhde is reversible, allowing preferenhal formahon of the thermodynamically more stable product from the Michael addihon. For example, the cyclopropane 112 is obtained from the reaction of dimethylsulfoxonium methylide with the enone 111 (1.105). Other methods for the formahon of cyclopropanes include carbene and Simmons-Smith-type... 

An unprecedented cyclopropenation reaction of alkynes catalyzed by ZnCl2 was reported. While Simmons-Smith-type carbenoids failed in the [2 + 1]-cycloaddition with alkynes, the use of enynones as the carbene source enabled the preparation of substituted 2-furyl cyclopropene derivatives with remarkable scope (14OL5780). 

A modified Simmons-Smith reaction has been used in the stereoselective synthesis of a naturally occurring substance called U-106305 containing six cyclopropane rings. In the synthesis, four of the six rings arise by Simmons-Smith-type cyclopropanation. The red lines in the structural formula identify the bonds to the CH2 groups that are introduced in this way the blue lines identify bonds that originated with the iiutial reactant. 

Interestingly, reaction of zirconacyclopentadienes with a Simmons-Smith type of carbene reagent afforded zirconacyclopentene-cyclopropane fused intermediates 26, which reacted further with CO to generate 1,2,3,5-tetra-substitued benzenes 27 via a novel skeletal rearrangement, as shown in Scheme 11.11 [12],... 

The chemistry and utility of zinc-based Lewis acids are similar to those of their magnesium analogs. Their mild Lewis acidity promotes several synthetic reactions, such as Diels-Alder reactions, hetero Diels-Alder reactions,229 radical-mediated reactions,230 ene-type cyclization, and Simmons-Smith reactions. 

Finally, it should be mentioned that from a purely synthetic point of view the reactions involving "transfer" of methylene groups -like the Simmons-Smith reaction [27] or Seyferth s reagents [28]- may be considered formally as cheletropic additions of a [2 + 1] type. 

Sulfur-stabilized copper-zinc carbanions have been used [299] by Knochel et at A first type obtained from the reaction of the Simmons-Smith reagent with a copper(i) thiolate was treated with a... 

Polymerization. Monomers. The cyclopropane type monomers are prepared either by addition of the dichlorocarbene or by the Simmons-Smith reaction on the corresponding olefins. Most of these compounds have been described. Spiropentane is prepared by the Applequist method (I, 2), by the reaction of zinc with C(CH2Br)4 in alcohol in the presence of ethylenediaminetetraacetic acid (EDTA). This hydrocarbon is purified until a single NMR signal is obtained at t = 9.28. 

Upon reaction with the Simmons-Smith reagent104) or m-chloroperbenzoic acid,105 cyclooctyne is transformed at least in part to products of the bicyclo-[3.3.0]octane type. 

A transition state of type (III) was suggested for the Simmons-Smith reaction on the basis of experimental observations 42, 456, 457, 459). 

This type of coordination is useful for highly stereoselective syntheses of cyclopropane derivatives. Reaction of A -cyclohexenyl methyl ether with the Simmons-Smith reagent gives CM-2-bicyclo[4.1.0]heptyl methyl ether without the trans isomer 103). The Simmons-Smith reaction with 7-tCT f-hutoxynorbornadiene gives syn-exo- IV) and syn-endo isomer (V) without the anti isomers 260). 

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